NORE1B, a candidate tumor suppressor, is epigenetically silenced in human hepatocellular carcinoma

Macheiner, Doris; Heller, Gerwin; Kappel, Sonja; Bichler, Christoph; Stättner, Stefan; Ziegler, Barbara; Kandioler, Daniela; Wrba, Fritz; Schulte‐Hermann, Rolf; Zöchbauer‐Müller, Sabine; Grasl‐Kraupp, Bettina

doi:10.1016/j.jhep.2005.12.017

Cited by 48 publications

(60 citation statements)

References 35 publications

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Section: Rassf1a Is Part Of a Family Of Potential Tumor Suppressorsmentioning

confidence: 99%

“…This protein demonstrates more restricted expression than RASSF5 and can form an endogenous complex with the Ras-related protein Rap. It regulates lymphocyte adhesion and has also been implicated as a tumor suppressor (Katagiri et al, 2003;Macheiner et al, 2006).RASSF2 is a pro-apoptotic Ras effector that is frequently downregulated in human tumors by promoter methylation, histone deacetylation and sometimes deletion (Akino et al, 2005; Endoh et al, 2005; Hesson et al, 2005; Lambros et al, 2005;Vos et al, 2003b). Inactivation of RASSF2 correlates with activation of Ras in tumor cells (Hesson et al, 2005).…”

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confidence: 99%

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The RASSF1A tumor suppressor

Donninger

Vos

Clark

2007

Journal of Cell Science

390

449

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RASSF1A lacks apparent enzymatic activity but contains a Ras association (RA) domain and is potentially an effector of the Ras oncoprotein. RASSF1A modulates multiple apoptotic and cell cycle checkpoint pathways. Current evidence supports the hypothesis that it serves as a scaffold for the assembly of multiple tumor suppressor complexes and may relay pro-apoptotic signaling by KRas. RASSF1A is part of a family of potential tumor suppressorsRASSF1A is a member of a family of six related proteins, each of which exhibits multiple splice variants. With the exception of some minor splice variants, each protein contains an RA domain and a C-terminal SARAH protein-protein interaction motif. Each family member, with the exception of RASSF3, has now been implicated as a human tumor suppressor. RASSF5 (Nore1a) is the best characterized member of the family after RASSF1A. RASSF5 was the first member of the family cloned and it was originally designated Nore1a for novel Ras effector 1 (Vavvas et al., 1998). RASSF5 binds activated Ras directly and is present in an endogenous complex with Ras in cells. RASSF5 is pro-apoptotic and kills cells in a Ras-dependent manner (Khokhlatchev et al., 2002;Vos et al., 2003a). It is frequently inactivated in human tumors by promoter methylation (Table 2). Moreover, it is linked to the development of a rare familial form of cancer (Chen et al., 2003), which confirms its role as a tumor suppressor in vivo. Its mechanisms of action remain largely unknown, although it may regulate the pro-apoptotic kinase MST1 (Praskova et al., 2004). A smaller splice version of RASSF5 has been identified and designated Nore1b or RAPL (Katagiri et al., 2003;Tommasi et al., 2002). This protein demonstrates more restricted expression than RASSF5 and can form an endogenous complex with the Ras-related protein Rap. It regulates lymphocyte adhesion and has also been implicated as a tumor suppressor (Katagiri et al., 2003;Macheiner et al., 2006).RASSF2 is a pro-apoptotic Ras effector that is frequently downregulated in human tumors by promoter methylation, histone deacetylation and sometimes deletion (Akino et al., 2005; Endoh et al., 2005; Hesson et al., 2005; Lambros et al., 2005;Vos et al., 2003b). Inactivation of RASSF2 correlates with activation of Ras in tumor cells (Hesson et al., 2005). Reintroduction of RASSF2 into tumor cells impairs tumorigenesis and knocking down RASSF2 enhances tumorigenesis (Akino et al., 2005). Thus, RASSF2 also appears to be an epigenetically inactivated tumor suppressor. The effector pathways controlled by it remain unknown.RASSF3 can also bind to Ras and inhibit cell growth (unpublished observations). However, it is the only family member whose RNA is not downregulated in tumors (Tommasi et al., 2002). Whether it is involved in tumor suppression thus remains unknown. RASSF4 is frequently downregulated by promoter methylation in human tumor cells, binds to Ras and induces apoptosis. It localizes mostly to the cytosol but can be recruited to the plasma membrane by activated Ras ...

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Section: Rassf1a Is Part Of a Family Of Potential Tumor Suppressorsmentioning

confidence: 99%

mentioning

confidence: 99%

The RASSF1A tumor suppressor

Donninger

Vos

Clark

2007

Journal of Cell Science

390

449

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“…Regarding liver cancer, reduced expression of the βE subunit was found in human HCC specimens as well as in N-nitroso morpholine-induced rat liver tumors [62,85] . Interestingly, activin βE expression was found to be regulated by the tumor suppressor gene RASSF1A [86] , a gene frequently inactivated by promoter hypermethylation in HCC [87,88] .…”

Section: Activin βCmentioning

confidence: 99%

Activins and activin antagonists in hepatocellular carcinoma

Deli

Kreidl²,

Santifaller³

et al. 2008

WJG

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“…We recently found epigenetic inactivation of the Ras effector genes NORE1B and RASSF1A in the majority of HCC due to CpG-site hypermethylation in the promoter regions. As a result, 97% of the 28 tumors studied revealed epigenetic inactivation of NORE1B, RASSF1A, or both (6). However, the Ras effector NORE1A was not affected by hypermethylation.…”

Section: Introductionmentioning

confidence: 94%

NORE1B Is a Putative Tumor Suppressor in Hepatocarcinogenesis and May Act via RASSF1A

et al. 2008

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Recently, we found epigenetic silencing of the Ras effector genes NORE1B and/or RASSF1A in 97% of the hepatocellular carcinoma (HCC) investigated. This is strong evidence that the two genes are of major significance in hepatocarcinogenesis. Although RASSF1A serves as a tumor suppressor gene, the functions of NORE1B are largely unknown. Here, we studied the role of NORE1B for growth and transformation of cells. To understand the molecular mechanisms of action of the gene, we used the wild-type form and deletion mutants without the NH 2 terminus and CENTRAL domain, the Ras association (RA) domain, or the COOH-terminal SARAH-domain. Intact RA and SARAH-domains were found to be necessary for NORE1B (a) to increase the G 0 -G 1 fraction in hepatoma cells, (b) to suppress c-Myc/Ha-Ras-induced cell transformation, and (c) to interact closely with RASSF1A, as determined with fluorescence resonance energy transfer. In further studies, cell cycle delay by NORE1B was equally effective in hepatocyte cell lines with wild-type or mutant Ras suggesting that NORE1B does not interact with either Ras. In conclusion, NORE1B suppresses replication and transformation of cells as effectively as RASSF1A and thus is a putative tumor suppressor gene. NORE1B interacts physically with RASSF1A and functional loss of one of the interacting partners may lead to uncontrolled growth and transformation of hepatocytes. This may explain the frequent epigenetic silencing of NORE1B and/or RASSF1A in HCC.

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NORE1B, a candidate tumor suppressor, is epigenetically silenced in human hepatocellular carcinoma

Cited by 48 publications

References 35 publications

The RASSF1A tumor suppressor

The RASSF1A tumor suppressor

Activins and activin antagonists in hepatocellular carcinoma

NORE1B Is a Putative Tumor Suppressor in Hepatocarcinogenesis and May Act via RASSF1A

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